Protocol of clinical population pharmacokinetics/pharmacodynamics analysis of alkaloids from the leaves of alstonia scholaris in acute bronchitis patients

Abstract

Objective: To validate whether orally administered Alkaloid Capsules from the leaves of Alstonia scholaris (CALAS) can improve the clinical indices of acute bronchitis and to investigate the alterations in the relationship between its composition and pharmacodynamic (PD) markers, thereby providing a clinical reference for the administration of this medication. Methods: This is a prospectively planned, blinded, placebo-controlled, parallel-grouped clinical trial with aggregated population pharmacokinetics/PD (PPK/PPD) data. A total of 55 subjects will be randomly allocated into four arms; specifically, 10 of the 55 subjects will be selected randomly for the placebo arm, and will be orally administered placebo (Tid), and 45 subjects will be randomly assigned to CALAS treatment groups (20 mg, 40 mg, and 80 mg Tid, at 15 subjects per group). The medication, presence of cough and phlegm, as well as body temperature of every subject will be recorded daily during treatment. About 3–4 blood samples will be collected from each subject at the following points for PPK/PPD parameters analysis: at pre-dose (0 h) and post-dose at 15 min, 40 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 30 h, and 48 h after last dosing. All the subjects will be subjected to a laboratory examination and efficacy evaluation on day 8. Discussion: A new integrating strategy to explore the relationship among drug components, action pathways, and clinical efficacy will be established through this study. We aim to explore the mechanism of action of CALAS in the treatment of acute bronchitis on the premise of definite active ingredients and reliable clinical efficacy. It is difficult to enrol patients in classical PK research because it adopts an intensive sampling method, and it cannot quantify the variability of PK parameters (Intra-individual variation, inter-individual variation and weekly variation). Moreover, the extrapolation and prediction of dosage regimens in different species and populations cannot be achieved. Therefore, the PPK/PPD method, which takes advantage of sparse data (3–5 time points sampling per patient), is adopted to determine the measurable pathological and physiological factors that can influence dose concentration to guide reasonable dose adjustment towards achieving optimal clinical effects.